The functions of the IL-36 cytokines remain poorly understood. We report a previously unrecognized mechanism whereby IL-36 promotes innate antiviral immunity in mouse and human models of herpes simplex virus-1 (HSV-1) infections. HSV-1 actively suppresses production of type I interferon (IFN); our data reveal that IL-36 overcomes this immune evasion strategy by increasing cellular sensitivity to IFN. IL-36β deficient mice display impaired IFN responses and poorly restrict viral replication in skin keratinocytes. In mouse and human keratinocytes IL-36 elicits an antiviral state driven by STAT1 and STAT2 via enhanced expression of IFNAR1 and IFNAR2 subunits of the type I IFN receptor. The degree of IFN regulatory factor 1 (IRF1) involvement is species dependent, with IRF1 playing a more prominent role in human cells. Similar mechanisms are activated by IL-1. Overall, IL-36 acts as an antiviral cytokine by potentiating type I IFN signaling and thereby upholds immune responses to viruses that limit the production of IFNs.

Because the vaccine-elicited antibody and neutralizing activity against spike protein of SARS-CoV-2 are associated with protection from COVID-19, it is important to determine the levels of specific IgG and neutralization titers against SARS-CoV-2 elicited by the vaccines. While three widely used vaccine brands (Pfizer-BNT162b2, Moderna-mRNA-1273 and Johnson-Ad26.COV2.S) are effective in preventing SARS-CoV-2 infection and alleviating COVID-19 illness, they have different efficacy against COVID-19. It is unclear whether the differences are due to varying ability of the vaccines to elicit a specific IgG antibody response and neutralization activity against spike protein of the virus. In this study, we compared the plasma IgG and neutralization titers against spike proteins of wild-type SARS-CoV-2 and eight variants in healthy subjects who received the mRNA-1273, BNT162b2 or Ad26.COV2.S vaccine. We demonstrated that subjects vaccinated with Ad26.COV2.S vaccine had significantly lower levels of IgG and neutralizing titers as compared to those who received the mRNA vaccines. While the linear regression analysis showed a positive correlation between IgG levels and neutralizing activities against SARS-CoV-2 WT and the variants, there was an overall reduction in neutralizing titers against the variants in subjects across the three groups. These findings suggest that people who received one dose of Ad26.COV2.S vaccine have a more limited IgG response and lower neutralization activity against SARS-CoV-2 WT and its variants than recipients of the mRNA vaccines. Thus, monitoring the plasma or serum levels of anti-SARS-CoV-2 spike IgG titer and neutralization activity is necessary for the selection of suitable vaccines, vaccine dosage and regimens.